1. P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells
- Author
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Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Rachna Prasad, Yue Qin, Maverick Johnson, Qing Wang, Nathan VanderVeer-Harris, Amy Pham, Alvaro G. Alvarado, Michael C. Condro, Fuying Gao, Raymond Gau, Maria G. Castro, Pedro R. Lowenstein, Arjun Deb, Jason D. Hinman, Frank Pajonk, Terry C. Burns, Steven A. Goldman, Daniel H. Geschwind, and Harley I. Kornblum
- Subjects
Multidisciplinary ,Neurosciences ,General Physics and Astronomy ,Glioma ,General Chemistry ,Stem Cell Research ,Chromatin ,General Biochemistry, Genetics and Molecular Biology ,Brain Disorders ,Brain Cancer ,Neoplasm Recurrence ,Rare Diseases ,Local ,Neoplastic Stem Cells ,Genetics ,Humans ,Stem Cell Research - Nonembryonic - Non-Human ,Neoplasm Recurrence, Local ,Histone Acetyltransferases ,Cancer - Abstract
Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.
- Published
- 2022